Application of thioglycoside chemistry to the synthesis of trisaccharides and deoxy-trisaccharides related to the Shigella flexneri Y polysaccharide

Abstract

The Shigella flexneri lipopolysaccharide has a biological repeating unit, → 2)α-L-Rhap(1→2)α-L-Rhap(1→3)α-L-Rhap(1→3)β-D-GlcNAcp(1 → ABCD, but the residue segment BCD suffices to fill the binding site of an O-antigen specific monoclonal antibody, SYA/J6. Synthetic modifications to this trisaccharide have been designed to investigate the involvement in binding of the acetamido moiety, the 4- and 6-OH groups of the GlcNAc residue D, the 4′-OH group of the Rha residue C, and the 3″- and 4″-OH groups of the Rha residue B. Sequential chain extension provided the protected trisaccharides 18, 24, 26, 28, 30, 32, and 35 using thioglycoside glycosyl donors activated by iodonium ions generated in situ from N-iodosuccinimide and triflic acid. Trisaccharides each monodeoxygenated in either ring B 25 and 27 or ring C 29 were accessed by the use of 3,6-dideoxy or 4,6-dideoxy glycosyl donors 14 and 17 and when these were used in sequential steps trisaccharides 31 and 33, each deoxygenated at double sites in adjacent residues, were obtained. Selective protection of the glucosamine residue as its N-benzyloxycarbonyl derivative provided a facile route to the trisaccharide amino compound 20, from which N-acetyl 21, N-propionyl 22, and N-trifluoroacetyl 23 derivatives were directly prepared. Orthoester intermediates were detected in several glycosylation reactions and culminated in an orthoacetate 34 as a major product rather than the target trisaccharide 35. When triflic acid concentration was increased these products were avoided but acid-catalyzed migration of a 2-O-acetyl group led to both 1→2 and 1→3 linked trisaccharides 35 and 37. To avoid similar undesirable 1,2-linked products, a block synthetic strategy using the 2-O-benzoylated disaccharide glycosyl donor 40 was chosen so that the propensity for orthoester formation was minimized in reactions leading to the trisaccharide analogue deoxygenated at C-6 of the glucosamine unit D.